J Pathol Transl Med.  2015 Sep;49(5):355-363. 10.4132/jptm.2015.07.29.

Current Issues and Clinical Evidence in Tumor-Infiltrating Lymphocytes in Breast Cancer

• Ahn SG
• Jeong J
• Hong S
• Jung WH

• KMID: 2381390
• DOI: http://doi.org/10.4132/jptm.2015.07.29

Abstract

With the advance in personalized therapeutic strategies in patients with breast cancer, there is an increasing need for biomarker-guided therapy. Although the immunogenicity of breast cancer has not been strongly considered in research or practice, tumor-infiltrating lymphocytes (TILs) are emerging as biomarkers mediating tumor response to treatments. Earlier studies have provided evidence that the level of TILs has prognostic value and the potential for predictive value, particularly in triple-negative and human epidermal growth factor receptor 2-positive breast cancer. Moreover, the level of TILs has been associated with treatment outcome in patients undergoing neoadjuvant chemotherapy. To date, no standardized methodology for measuring TILs has been established. In this article, we review current issues and clinical evidence for the use of TILs in breast cancer.

Keyword

Breast neopalsms; Immune system; Lymphocytes, tumor-infiltrating; Triple negative breast neoplasms

MeSH Terms

Biomarkers
Breast Neoplasms*
Breast*
Drug Therapy
Humans
Immune System
Lymphocytes, Tumor-Infiltrating*
Negotiating
Receptor, Epidermal Growth Factor
Treatment Outcome
Triple Negative Breast Neoplasms
Receptor, Epidermal Growth Factor

Reference

1. Heemskerk B, Kvistborg P, Schumacher TN. The cancer antigenome. EMBO J. 2013; 32:194–203.

2. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015; 348:69–74.

3. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013; 500:415–21.

4. Loi S, Michiels S, Salgado R, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol. 2014; 25:1544–50.

5. Mahmoud SM, Paish EC, Powe DG, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011; 29:1949–55.

6. Menard S, Tomasic G, Casalini P, et al. Lymphoid infiltration as a prognostic variable for early-onset breast carcinomas. Clin Cancer Res. 1997; 3:817–9.

7. Mohammed ZM, Going JJ, Edwards J, Elsberger B, Doughty JC, McMillan DC. The relationship between components of tumour inflammatory cell infiltrate and clinicopathological factors and survival in patients with primary operable invasive ductal breast cancer. Br J Cancer. 2012; 107:864–73.

8. Tomsova M, Melichar B, Sedlakova I, Steiner I. Prognostic significance of CD3+ tumor-infiltrating lymphocytes in ovarian carcinoma. Gynecol Oncol. 2008; 108:415–20.

9. Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003; 348:203–13.

10. de Jong RA, Leffers N, Boezen HM, et al. Presence of tumor-infiltrating lymphocytes is an independent prognostic factor in type I and II endometrial cancer. Gynecol Oncol. 2009; 114:105–10.

11. Giatromanolaki A, Bates GJ, Koukourakis MI, et al. The presence of tumor-infiltrating FOXP3+ lymphocytes correlates with intratumoral angiogenesis in endometrial cancer. Gynecol Oncol. 2008; 110:216–21.

12. Ino K, Yamamoto E, Shibata K, et al. Inverse correlation between tumoral indoleamine 2,3-dioxygenase expression and tumor-infiltrating lymphocytes in endometrial cancer: its association with disease progression and survival. Clin Cancer Res. 2008; 14:2310–7.

13. Kondratiev S, Sabo E, Yakirevich E, Lavie O, Resnick MB. Intratumoral CD8+ T lymphocytes as a prognostic factor of survival in endometrial carcinoma. Clin Cancer Res. 2004; 10:4450–6.

14. Yamagami W, Susumu N, Tanaka H, et al. Immunofluorescence-detected infiltration of CD4+FOXP3+ regulatory T cells is relevant to the prognosis of patients with endometrial cancer. Int J Gynecol Cancer. 2011; 21:1628–34.

15. Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014; 20:5064–74.

16. Galon J, Angell HK, Bedognetti D, Marincola FM. The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity. 2013; 39:11–26.

17. Coussens LM, Pollard JW. Leukocytes in mammary development and cancer. Cold Spring Harb Perspect Biol. 2011; 3:a003285.

18. Gobert M, Treilleux I, Bendriss-Vermare N, et al. Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res. 2009; 69:2000–9.

19. Gu-Trantien C, Loi S, Garaud S, et al. CD4(+) follicular helper T cell infiltration predicts breast cancer survival. J Clin Invest. 2013; 123:2873–92.

20. Ruffell B, Au A, Rugo HS, Esserman LJ, Hwang ES, Coussens LM. Leukocyte composition of human breast cancer. Proc Natl Acad Sci U S A. 2012; 109:2796–801.

21. Cimino-Mathews A, Ye X, Meeker A, Argani P, Emens LA. Metastatic triple-negative breast cancers at first relapse have fewer tumor-infiltrating lymphocytes than their matched primary breast tumors: a pilot study. Hum Pathol. 2013; 44:2055–63.

22. Gutcher I, Becher B. APC-derived cytokines and T cell polarization in autoimmune inflammation. J Clin Invest. 2007; 117:1119–27.

23. Abbas AK, Benoist C, Bluestone JA, et al. Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol. 2013; 14:307–8.

24. Liu S, Lachapelle J, Leung S, Gao D, Foulkes WD, Nielsen TO. CD8+ lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer. Breast Cancer Res. 2012; 14:R48.

25. Seo AN, Lee HJ, Kim EJ, et al. Tumour-infiltrating CD8+ lymphocytes as an independent predictive factor for pathological complete response to primary systemic therapy in breast cancer. Br J Cancer. 2013; 109:2705–13.

26. Liu F, Lang R, Zhao J, et al. CD8(+) cytotoxic T cell and FOXP3(+) regulatory T cell infiltration in relation to breast cancer survival and molecular subtypes. Breast Cancer Res Treat. 2011; 130:645–55.

27. Teschendorff AE, Gomez S, Arenas A, et al. Improved prognostic classification of breast cancer defined by antagonistic activation patterns of immune response pathway modules. BMC Cancer. 2010; 10:604.

28. Qi W, Huang X, Wang J. Correlation between Th17 cells and tumor microenvironment. Cell Immunol. 2013; 285:18–22.

29. Bates GJ, Fox SB, Han C, et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol. 2006; 24:5373–80.

30. West NR, Kost SE, Martin SD, et al. Tumour-infiltrating FOXP3(+) lymphocytes are associated with cytotoxic immune responses and good clinical outcome in oestrogen receptor-negative breast cancer. Br J Cancer. 2013; 108:155–62.

31. Anz D, Eiber S, Scholz C, et al. In breast cancer, a high ratio of tumour-infiltrating intraepithelial CD8+ to FoxP3+ cells is characteristic for the medullary subtype. Histopathology. 2011; 59:965–74.

32. Miyashita M, Sasano H, Tamaki K, et al. Tumor-infiltrating CD8+ and FOXP3+ lymphocytes in triple-negative breast cancer: its correlation with pathological complete response to neoadjuvant chemotherapy. Breast Cancer Res Treat. 2014; 148:525–34.

33. An T, Sood U, Pietruk T, Cummings G, Hashimoto K, Crissman JD. In situ quantitation of inflammatory mononuclear cells in ductal infiltrating breast carcinoma: relation to prognostic parameters. Am J Pathol. 1987; 128:52–60.

34. Mahmoud SM, Lee AH, Paish EC, Macmillan RD, Ellis IO, Green AR. The prognostic significance of B lymphocytes in invasive carcinoma of the breast. Breast Cancer Res Treat. 2012; 132:545–53.

35. Schmidt M, Hellwig B, Hammad S, et al. A comprehensive analysis of human gene expression profiles identifies stromal immunoglobulin kappa C as a compatible prognostic marker in human solid tumors. Clin Cancer Res. 2012; 18:2695–703.

36. Martinet L, Garrido I, Filleron T, et al. Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res. 2011; 71:5678–87.

37. Martinet L, Filleron T, Le Guellec S, Rochaix P, Garrido I, Girard JP. High endothelial venule blood vessels for tumor-infiltrating lymphocytes are associated with lymphotoxin beta-producing dendritic cells in human breast cancer. J Immunol. 2013; 191:2001–8.

38. Melichar B, Ferrandina G, Verschraegen CF, Loercher A, Abbruzzese JL, Freedman RS. Growth inhibitory effects of aromatic fatty acids on ovarian tumor cell lines. Clin Cancer Res. 1998; 4:3069–76.

39. Jacquemier J, Bertucci F, Finetti P, et al. High expression of indoleamine 2,3-dioxygenase in the tumour is associated with medullary features and favourable outcome in basal-like breast carcinoma. Int J Cancer. 2012; 130:96–104.

40. Dong DD, Yie SM, Li K, et al. Importance of HLA-G expression and tumor infiltrating lymphocytes in molecular subtypes of breast cancer. Hum Immunol. 2012; 73:998–1004.

41. Hornychova H, Melichar B, Tomsova M, Mergancova J, Urminska H, Ryska A. Tumor-infiltrating lymphocytes predict response to neoadjuvant chemotherapy in patients with breast carcinoma. Cancer Invest. 2008; 26:1024–31.

42. Denkert C, Loibl S, Noske A, et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010; 28:105–13.

43. Salgado R, Denkert C, Demaria S, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015; 26:259–71.

44. West NR, Milne K, Truong PT, Macpherson N, Nelson BH, Watson PH. Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer. Breast Cancer Res. 2011; 13:R126.

45. Loi S, Sirtaine N, Piette F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013; 31:860–7.

46. Adams S, Gray RJ, Demaria S, et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol. 2014; 32:2959–66.

47. Liu S, Foulkes WD, Leung S, et al. Prognostic significance of FOXP3+ tumor-infiltrating lymphocytes in breast cancer depends on estrogen receptor and human epidermal growth factor receptor-2 expression status and concurrent cytotoxic T-cell infiltration. Breast Cancer Res. 2014; 16:432.

48. Ali HR, Provenzano E, Dawson SJ, et al. Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann Oncol. 2014; 25:1536–43.

49. Schalper KA, Velcheti V, Carvajal D, et al. In situ tumor PD-L1 mRNA expression is associated with increased TILs and better outcome in breast carcinomas. Clin Cancer Res. 2014; 20:2773–82.

50. Perez EA, Ballman KV, Anderson SK, et al. Stromal tumor-infiltrating lymphocytes (S-TILs): in the alliance N9831 trial S-TILs are associated with chemotherapy benefit but not associated with trastuzumab benefit. In : San Antonio Breast Cancer Symposium (SABCS); 2014 Dec 2; Redwood, CA, USA. Abstract S1-06.

51. Denkert C, von Minckwitz G, Brase JC, et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J Clin Oncol. 2015; 33:983–91.

52. Ono M, Tsuda H, Shimizu C, et al. Tumor-infiltrating lymphocytes are correlated with response to neoadjuvant chemotherapy in triple-negative breast cancer. Breast Cancer Res Treat. 2012; 132:793–805.

53. Yamaguchi R, Tanaka M, Yano A, et al. Tumor-infiltrating lymphocytes are important pathologic predictors for neoadjuvant chemotherapy in patients with breast cancer. Hum Pathol. 2012; 43:1688–94.

54. Oda N, Shimazu K, Naoi Y, et al. Intratumoral regulatory T cells as an independent predictive factor for pathological complete response to neoadjuvant paclitaxel followed by 5-FU/epirubicin/cyclophosphamide in breast cancer patients. Breast Cancer Res Treat. 2012; 136:107–16.

55. Issa-Nummer Y, Darb-Esfahani S, Loibl S, et al. Prospective validation of immunological infiltrate for prediction of response to neoadjuvant chemotherapy in HER2-negative breast cancer--a substudy of the neoadjuvant GeparQuinto trial. PLoS One. 2013; 8:e79775.

56. Lee HJ, Seo JY, Ahn JH, Ahn SH, Gong G. Tumor-associated lymphocytes predict response to neoadjuvant chemotherapy in breast cancer patients. J Breast Cancer. 2013; 16:32–9.

57. Nabholtz JM, Abrial C, Mouret-Reynier MA, et al. Multicentric neoadjuvant phase II study of panitumumab combined with an anthracycline/taxane-based chemotherapy in operable triple-negative breast cancer: identification of biologically defined signatures predicting treatment impact. Ann Oncol. 2014; 25:1570–7.

58. Shah SP, Roth A, Goya R, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature. 2012; 486:395–9.

59. Perez EA, Thompson EA, Ballman KV, et al. Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group n9831 Adjuvant Trastuzumab Trial. J Clin Oncol. 2015; 33:701–8.

60. Mao Y, Qu Q, Zhang Y, Liu J, Chen X, Shen K. The value of tumor infiltrating lymphocytes (TILs) for predicting response to neoadjuvant chemotherapy in breast cancer: a systematic review and meta-analysis. PLoS One. 2014; 9:e115103.